It is believed that cholinergic hypofunction contributes to the cognitive deficits associated with Alzheimer's disease (Science, 1982, 215, 1237-1239) and acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, are used clinically for the treatment of cognitive impairment in Alzheimer's disease. Cholinergic deficits are also prominent in dementia with Lewy bodies (DLB) and when administered to patients with DLB the cholinesterase inhibitor donepezil has been reported to give significant improvements in behavioural measures (Ann. Neurol., 2012, 72(1), 41-52). Therefore, activation of central cholinergic neurotransmission via enhanced signalling of muscarinic receptors may be effective for the symptomatic treatment of cognitive deficits associated with neurological disorders such as AD or DLB.
Muscarinic acetylcholine receptors are G-protein coupled receptors that mediate the actions of the neurotransmitter acetylcholine. Five distinct mammalian mAChR subtypes (M1-M5) have been identified in mammals. mAChR M1 which is predominantly expressed in the cortex, hippocampus and striatum, has been found to have an important role in cognitive processing (Psychopharmacology, 1987, 93, 470-476; Behav. Brain Res. 1988, 27, 9-20; Nature Neuroscience, 2002, 6, 51-58) and, more recently, has also been implicated as having a potential role in modifying Alzheimer's disease progression (Proc. Natl. Acad. Sci. USA, 1992, 89, 10075-10078). However, other muscarinic subtypes, in addition to being expressed centrally are also expressed peripherally e.g. mAChR M2 is expressed in cardiac tissue and in smooth muscle whilst mAChR M3 is expressed in sweat and salivary glands (Pharmacology and Therapeutics, 2008, 117, 232). As a result, muscarinic activation by non-selective agonists has resulted in dose-limiting peripheral cholinergic side-effects which may be attributed to their relative lack of selectivity. Selective mAChR M1 activation may therefore prove useful in the treatment of cognitive impairment, including diseases such as Alzheimer's disease and DLB, as well as for the treatment of cognitive disorders associated with psychotic disorders such as schizophrenia, but without the peripheral cholinergic side-effects mediated predominantly through mAChR M2 and mAChR M3.
Since the orthosteric acetylcholine binding site is highly conserved across the muscarinic family, obtaining selective mAChR M1 orthosteric ligands may prove challenging. However, recent advances in the understanding of alternative binding motifs and receptor states (Trends in Pharmacological Sciences, 2009, 30, 460-469) has identified the possibility of allosteric binding sites which are distinct from the endogenous ligand site and thus potentially much less conserved across the family. mAChR M1 is known to contain one or more such allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or orthosteric sites or affect downstream signalling (Molecular Pharmacology, 2000, 58, 194-207; Molecular Pharmacology, 2002, 62, 1492-1505). Positive Allosteric Modulators (PAM) of mAChR M1 are thus expected to be useful in enhancing muscarinic receptor function in a selective fashion, avoiding many of the potential side effects associated with activation of other muscarinic subtypes (Trends in Pharmacological Sciences, 2009, 30, 148-155).
mAChR M1PAM compounds have been investigated as potential therapies for cognitive impairment associated with neurological disorders such as dementia (for example dementia associated with Alzheimer's disease), mild cognitive impairment and age related cognitive decline and also for psychiatric disorders such as schizophrenia, for example as described in WO2009094279, WO2011075371, WO2012158473, WO2013063549 and WO2013091773.
Examples of other diseases that might be treatable or preventable with a compound which acts as a modulator of mAChR M1 are: Huntington's disease, amyotrophic lateral sclerosis (ALS), post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, Down's syndrome, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), cognitive disorders related to drug abuse including cocaine abuse, cognitive disorders related to nicotine withdrawal, autism, dementia, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, fragile-X syndrome, autism-spectrum disorders, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, positive or negative or cognitive symptoms of schizophrenia, sleep disorders, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium, sleep disturbances, synucleinopathies, alpha-synucleinopathies, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and other neurodegenerative diseases.